Canadian Association for the Study of the Liver CASL ACEF Association Canadienne pour l étude du foie CDDW DIGEST 2014 Canadian Digestive Diseases Week and the Annual CASL Winter Meeting Toronto, Ontario February 8-11, 2014 Table of Contents: Diet and Nutrition in Gastrointestinal Health...1 Microbiome...2 Liver Transplantation...3 Acute on Chronic Liver Failure...4 Gastrointestinal Bleeding...5 IBD: Ulcerative Colitis...6
Diet and Nutrition in Gastrointestinal Health Session co-chaired by Dr. David Armstrong (McMaster University) and Dr. Levinus Dieleman (University of Alberta). Diet and Nutrition in Gastrointestinal Health 1 Nutritional Health in Canada Mind the Gap The negative impact of malnutrition on patient health is undeniable, yet Dr. Leah Gramlich (University of Alberta) presented data showing a lack of awareness among healthcare professionals regarding malnutrition in Canadian hospitals. Malnutrition has a substantial impact on healthcare, resulting in patients being 6x more likely to die and 1.61x more likely to be readmitted. Almost half of patients entering Canadian hospitals meet the criteria for malnutrition, highlighting the need for patient screening and intervention strategies. Established in 2010, the Canadian Malnutrition Task Force (CMTF), of which Dr. Gramlich is a member, aims to prevent, detect and treat malnutrition among patients in Canada. Priorities of the CMTF include establishing standardized screening procedures, optimizing food and nutrition services in hospitals and involving a multidisciplinary team in the nutritional care of patients. Nutrition and the GI Tract The Diet-Microbiome Axis Continuing with nutrition and health, Dr. Levinus Dieleman (University of Alberta) discussed the role of the gut microbiota in this complex relationship. The Western diet has become increasingly unhealthy over the last 50 years, correlating with an increase in gastrointestinal (GI)-related disorders. The gut microflora of people in Western civilization (eating a diet high in animal protein, fat, sugar and starch, and low in fiber) differs significantly from that of individuals who consume an agrarian diet (rich in carbohydrates, fiber and non-animal protein) and has relatively lower microbial diversity (an observation that can be recapitulated in laboratory mice). Several striking examples of research showing how diet can directly effect the composition and functioning of the human microbiome were presented. Dietary therapy, in the context of the human gut microbiome, could be a viable treatment for patients in the early stages of GI disease or as a measure to prevent disease. Elafin Delivery by Recombinant Lactococci for Intestinal Barrier Fortification: A Potential Adjuvant Therapy for Gluten-related Disorders One of the hallmarks of inflammatory bowel disease (IBD) is a measureable decrease in patient tissues of elafin, an anti-inflammatory protease inhibitor. Research presented by Justin McCarville (McMaster University) showed elafin levels are reduced in the lower intestines of patients with celiac disease (CD). Elafin inhibited transglutaminase 2-dependent gliadin deamidation (a critical step in CD progression) in vitro, and elafin delivery (via an engineered elafin-producing bacterial strain), in an in vivo gluten-sensitive mouse model, prevented small intestine barrier dysfunction and inflammation induced by gliadin. Based on these findings, elafin supplementation may have potential as an adjuvant therapy to a gluten-free diet for the treatment of CD. Gut Microbiota and Susceptibility to Inflammation in a Maternal Separation Model of Depression Research presented by Dr. Giada De Palma (McMaster University) examined the role of the gut microbiota in intestinal colitis susceptibility and mood disorders, the latter a common comorbidity of IBD. Using a maternal separation (MS) mouse model of early-life stress, it was shown that germ-free (GF) MS mice did not display alterations in mood, in contrast to MS mice with a normal gut microflora. In both MS mice populations, hypothalamic-pituitary-adrenal (HPA) activity was higher. Finally, adult GF MS mice displayed an increased susceptibility to experimental colitis and exhibited anxiety- and depression-like behaviour when colonized with the microbiota of MS mice. The altered behaviour and increased vulnerability to colitis in MS mice are microbiotadependent, while changes in HPA activity are independent of the gut microbiota. Nutrition and the Gastroenterologist Putting Science into Practice Dr. Sheila Crowe (University of California, San Diego) discussed an array of topics concerning health and nutrition. There has been a significant increase in the frequency of patients with food allergies, food-related diseases (such as CD) and food sensitivities in general. A number of factors from early life influence the risk of developing GI disorders, and differences between adverse food reactions that are immune-mediated (allergy, CD) and non-immune-mediated (food intolerance) were discussed (see Figure 1). Figure 1. Classification of Adverse Reactions to Food IgE (OAS, Hives, Anaphylaxis) Mixed (EoE) Adverse food reaction Immune Non-IgE (FPIES, Celiac) Cell (Allergic contact dermatitis) Metabolic (Lactose intolerance) Toxic (Scombroid) Non-immune Adapted from: Boyce JA et al. JACI. 2010 126:S1-58. Pharmacological (Tyramine) Other (Mechanical, physiological) There are a number of diets for treating functional GI disorders, but there is limited data to support their efficacy. The low FODMAP diet (dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates [fermentable, oligo-, di-, monosaccharides, and polyols]) is based on the concept that certain starches are fermented differently by different microbiomes and benefits patients with irritable bowel syndrome. This concept of personalized dietary treatment is the next frontier in treating functional GI disorders.
Microbiome Session co-chaired by Dr. Premysl Bercik (McMaster University) and Dr. Bruce Vallance (University of British Columbia). The Role of Intestinal Microbiota in IBS Dr. Josh Neufeld (University of Waterloo) highlighted advances in nucleic acid sequencing technologies that allow for a more detailed examination of the microbiome, and introduced the software program, AXIOME (Lynch et al., 2013), which enables the robust analysis of the abundant data from these approaches. Dr. Neufeld presented results from a collaborative study with Dr. Premysl Bercik (McMaster University) showing a high degree of inter-individual microbiome variability in individuals with irritable bowel syndrome (IBS). The microbiomes of IBS individuals were routinely found to include members of the Firmicutes and Lachnospiraceae; although it is not known whether the presence of these microbes is causal or a result of IBS. Fecal transplants from human IBS patients into mice could transfer the symptoms associated with IBS, including depression-like behaviour, which is a comorbidity of IBS. Transplantation of Dysbiotic Microbiota Derived from IBD Patients Promotes a Proinflammatory Phenotype and Increased Susceptibility of Gnotobiotic Mice to Colitis The causal relationship between disturbances of the gut microbiota (dysbiosis) and ulcerative colitis (UC) was explored in research presented by Dr. Jane Natividad (McMaster University). When gut microbiota from healthy and UC patients were used to colonize GF mice, the composition of the microbiome in UC recipient mice was more variable in comparison to mice receiving healthy microbiota. In both recipient groups, induction of regulatory T cells and Th17 cells was observed, but was more pronounced in UC recipient mice. UC recipient mice were more prone to experimentally induced intestinal injury, which was associated with higher histological scores, myeloperoxidase activity and pro-inflammatory cytokine activity. This work showed that UC-associated intestinal dysbiosis may have an important causal role in intestinal inflammation. Human Gut Microbiota, Diet and IBD Dr. Gary Wu (University of Pennsylvania) discussed how diet can modify the gut microbiome to improve health. Diet directly influences microbiome composition and provides substrates for microorganisms to produce molecules that impact human health. A prominent example of such metabolic-interplay was detailed in work by Koeth et al. (2013), showing that intestinal bacteria can metabolize red meat-derived L-carnitine into trimethylamine-n-oxide, a compound that promotes atherosclerosis in humans. The CaFE study (Wu et al., 2011) examined the relationship between diet and microbiome composition, revealing that diet can lead to modest, yet significant changes to the gut microbiota in <24 hrs; however, more time is needed (>10 days) for diet to cause considerable microbiome alterations. Work by Claessen et al. (2012) showed dramatic changes in the gut microbiome can occur within 1 year, as evidenced by an analysis of elderly individuals moved into long-term care facilities. The ongoing PLEASE is monitoring microbiome changes in pediatric IBD patients on an elemental diet (protein in the form of amino acids, very low in fat, and other easily digestible nutrients, minerals and vitamins), to identify alterations to the microbiome that correlate with successful/failed diet therapy. More human functional studies are needed if microbiome research is to realize its full potential. Hydrogen Sulfide Alters Gut Bacterial Growth and Diversity, and Stimulates Host Mucosal Immunity Hydrogen sulphide (H 2 S) is known to have a protective effect in the gastrointestinal (GI) tract, promoting resolution of inflammation and repair of intestinal injury in colitis models through an unknown mechanism. Dr. Jean-Paul Motta (University of Calgary) presented research suggesting H 2 S stimulates mucosal immunity by modifying the gut microbiota. Through in vitro techniques, H 2 S was found to promote the formation of biofilms by gut microbiota, while inhibiting their planktonic growth. In vivo, mice developed less severe, experimentally induced, colitis when given an H 2 S donor twice daily intracolonically. Colitis was associated with severe disruptions in microbial biofilms and caused bacterial translocation, however, this was not observed in mice given an H 2 S donor. An increase in mucous granules and colonic crypts, and altered expression of epithelial antimicrobial peptides, were also observed in the H 2 S mice. This suggests H 2 S can inhibit the growth of some intestinal bacteria and may alter the composition of the gut microbiome through modulation of the host mucosal immune response. Microbiota and Gut Inflammation: Lessons from Animal Models Dr. Eytan Wine (University of Alberta) discussed mouse model systems currently used for microbiome IBD studies. Their utility in helping to answer basic biological questions was highlighted in a study by Cahenzil et al. (2013), showing that exposure to a diverse and critical-mass of microbes during early life is necessary for the stimulation of a normal (life-long) gut immune response. Using humanized mice (germ-free mice colonized with human fecal microbiota), Kashyap et al. (2013) showed how diet can affect GI transit times, and that changes in the microbiota can impact gut motility. Fecal transplantation was proposed as a tool for investigating causality in relation to microbes and disease. A study by Ridaura et al. (2013) demonstrated how microbiota transplanted from obese or lean humans can induce similar phenotypes in recipient mice. IBD is not a single disease, but includes multiple, phenotypically similar conditions; thus no single model can universally explain the role of the gut microbiota in IBD. Microbiome 2
Liver Transplantation Session co-chaired by Dr. Paul Marotta (Western University) and Dr. Eberhard Renner (University of Toronto) Current Status of Live Donor Liver Transplantation in Canada Dr. Eberhard Renner discussed live donor liver transplantation (LDLT), an alternative to deceased donor liver transplantation, which helps combat the donor supply/demand gap. He reviewed the LDLT procedure (see Figure 2), noting that left lobe liver transplantation is rarely performed due to greater risk of complications. He emphasized that donor safety is the priority, requiring separate management teams for the donor and recipient to ensure no conflicts of interest. Figure 2. Live donor liver transplantation discussed considerations and precautions for liver transplantation in patients with HIV. The majority of these patients are co-infected with hepatitis C virus (HCV) or hepatitis B virus (HBV). She emphasized the importance of early referral due to a more complicated patient work-up involving coordination with HIV specialists. Proper patient selection impacts outcomes. Factors that predict liver-related deaths post-transplantation, such as MELD and Child-Pugh scores, are similar between patients with HIV infection and those without. Interestingly, patients who have not received ART prior to liver transplantation are more likely to suffer a liver-related death after the first decompensation. Historically, higher rates of graft rejection have been observed in HIV infected patients. Although unclear why, this may be due to drug-drug interactions (DDIs) between ART and immunosuppressive drugs. Liver Transplantation Portion of liver is removed...and transplanted to recipient. From the perspective of the recipient, LDLT is associated with shorter waitlist times and a 20% greater chance of survival after 5-years from the time of waitlist entry compared to deceased donor liver transplantation. He noted 1-year survival rates post-transplantation are similar between both donor sources. From the time of waitlist entry, recipients of LDLT have a 20% higher probability of 5-year survival compared to deceased donor transplantation recipients. - Dr. Eberhard Renner Although LDLT is an attractive option, live donation must be voluntary and altruistic, and not all recipients will appeal to a live donor. Recipients who evoke sympathy, such as those who are younger in age, married, suffering from an auto-immune disease or especially those who are visibly sick, are more likely to obtain a live donor. Survival rates post-liver transplantation are dependent on whether the patient is co-infected with HBV or HCV. Patients with HBV have better survival and lower rates of recurrent infection due to the ability to control the HBV infection prior to transplantation. The prognosis for patients with HCV is improving with the emergence of new direct-acting antivirals. Anecdotally, after 4 weeks of treatment with sofosbuvir the majority of Dr. Terrault s patients have undetectable HCV levels. The ability to control HCV infection, combined with a shift towards ART with fewer DDIs, is thought to further improve the 5-year prognosis for patients with HIV post-liver transplantation. Indication for Combined Liver and Kidney Transplantation Kidney disease is highly prevalent in patients with liver disease, with an increasing subset of patients requiring simultaneous liver-kidney transplantation (SLK). Dr. Joseph Kim (University of Toronto) discussed the indications and considerations for SLK, noting large practice variation and a lack of standardized eligibility criteria. 3 From the perspective of the donor, Dr. Renner said some degree of risk will always exist, with the current donor mortality rate reported to be 0.2% (believed to be 0.3% due to underreporting of mortality). He highlighted that risk is mitigated through experienced teams, established protocols, rigorous donor selection and expert medical and surgical care posttransplantation. Donors have a 40% morbidity rate, with a low occurrence of serious complications. Patients have excellent recovery in the range of 1 to 3 months, and 80% of donors found the process rewarding and would do it again. HIV and Liver Transplantation With current antiretroviral therapy (ART), the lifespan of patients with HIV is prolonged and comorbidities such as liver disease are increasing in relevance. Death from liver disease is the leading cause of mortality among patients with controlled HIV, leading to an increased need for liver transplantation in these patients. Dr. Norah Terrault (University of California) It is important to identify patients suitable for SLK early, as outcomes for patients who develop end-stage renal disease (ESRD) post-liver transplantation are poor. A staged liverkidney transplantation, where kidney transplantation is performed a short time after liver transplantation, may be considered for some patients. Dr. Kim reviewed the published guidelines and policies for SLK eligibility, emphasizing that the decision is made by multiple teams and involves an integrated assessment of acute versus chronic kidney injury, duration of injury and severity. The importance of determining reversibility of kidney injury using glomerular filtration rate (GFR) in clinically optimal patients, ultrasounds, and/or kidney biopsies, was discussed. Although helpful, a kidney biopsy may not be suitable for all patients and is unsafe in patients with ESRD. Patients on dialysis for >3 months are considered eligible for kidney transplantation, as this is a sign of irreversible kidney failure.
Acute-on-chronic Liver Failure Session co-chaired by Dr. Puneeta Tandon (University of Alberta) and Dr. Phil Wong (McGill University) The Syndrome and the Natural History Dr. Julia Wendon (King s College London) discussed acuteon-chronic liver failure (ACLF), an acute deterioration in patients with chronic liver disease associated with a high risk of short-term mortality (see Figure 3). There are inconsistencies in the definitions put forth by the Asia-Pacific Association for the Study of the Liver (APASL) and the American Association for the Study of Liver Disease/European Association for the Study of the Liver (AASLD/EASL). She noted these definitions are not evidence-based. Figure 3. Concept of ACLF % Survival Acute insult Time Recover and survive Organ Failure Chronic liver disease Data was presented from CANONIC, the first evidence-based study designed to define and identify patients with ACLF. This study developed criteria to define ACLF according to five groups (No ACLF, or ACLF grade 1 to 4) with increasing mortality risk (full definitions of the ACLF classifications can be found in Gastroenterology. 2013;144:1426). Mortality risk increases with organ failure, which is assessed using a modified sequential organ failure assessment score (SOFA-CLIF), placing a greater focus on the liver. Patients with ACLF, who survive an acute deterioration (AD), have a lower probability of death than ACLF patients with no prior AD. Dr. Wendon described causes of AD identified in CANONIC, noting cause is unknown in 40% of patients with ACLF. Gastrointestinal bleeding was no longer considered to be a precipitant of AD, likely due to the improved management of these patients. Further investigations are needed to determine whether the precipitating cause of the disease differentiates subgroups of ACLF. The Difficult Issue of Futile vs. Non-futile Intensive Care Dr. Dean Karvellas (University of Alberta) discussed futile versus non-futile intensive care, noting the lack of an evidencebased therapeutic window for critically ill cirrhotic patients. Without proper guidance, it becomes challenging to assess appropriate patient care and discuss with family members of the critically ill. Variceal bleeding, encephalopathy, septic shock or acute kidney injury are the main reasons a cirrhotic patient presents to intensive care with organ failure. New treatment approaches are improving mortality associated with variceal bleeding, such as restrictive transfusion strategies and early use of transjugular intrahepatic portosystemic shunts. The importance of early and appropriate initial antimicrobial therapy was highlighted, as bacteraemia and time of to-of-appropriate antimicrobial therapy were independent predictors of worse patient outcomes. There are limitations with the prognostic scoring systems for critically ill cirrhotic patients; organ/intensive care unit (ICU)-based scores (SOFA, APACHE II) perform better than liver-specific scores (MELD, Child-Pugh). Although these scores are able to stratify candidates for transplantation, predicting outcomes for critically ill patients is more difficult and can impact resource utilization, length of hospital stay and complications post-transplantation. Data was presented showing ICU readmittance after transplantation was associated with a significantly worse patient outcome. Long-term health recovery is an important consideration, with renal recovery and delirium prominent challenges for this group of patients. Independent predictors for developing delirium were highlighted, including: severity of illness according to APACHE II; renal replacement pre-transplantation; and necessity for transfusions at the time of transplantation. Irrespective of cause, delirium is associated with an increased risk of in-hospital and 1-year mortality. How to Prevent Complete Kidney Failure in Cirrhotic Patients Renal dysfunction in patients with cirrhosis is common, with hepatorenal syndrome (HRS) considered to be the most serious and life-threatening form. Dr. Florence Wong (University of Toronto) reviewed the types of renal failure observed in cirrhotic patients, noting HRS occurs in a specific, well-defined group of patients. In patients with cirrhosis, small rises in serum creatinine are significant, even if they remain within normal limits. A small rise is defined as a 50% increase in serum creatinine from baseline or an increase of 0.3 mg/dl. Data was presented which demonstrated significantly decreased survival in these patients compared to patients without acute kidney injury. Even minimal renal dysfunction in a cirrhotic patient has a negative impact on survival, and increases in patient mortality are correlated with a progressive loss of renal dysfunction. Dr. Wong provided an overview of the reasons for renal failure in cirrhotic patients, noting the cirrhotic liver is primed to cause renal failure due to the activation of renal vasoconstrictor systems. As such, bacterial infections and large volume paracentesis without colloid solution, which ultimately promote renal vasoconstriction, are precipitating factors for renal failure in these patients. Strategies to prevent or overcome vasoconstriction therefore have a role for preventing renal failure. Several studies demonstrate the use of albumin, pentoxifylline and rifaximin for reducing the incidence of renal failure/hrs or improving survival. Clinicians need to be vigilant in detecting the development of renal dysfunction in cirrhotic patients, as preventative, early treatment can be life saving. Acute on Chronic Liver Failure 4
Gastrointestinal Bleeding Session co-chaired by Dr. Alan Barkun (McGill University) and Dr. Lawrence Hookey (Queen s University). Gastrointestinal Bleeding 5 Upper GI Bleeding Upper GI bleeding anti-platelet agents Dr. Frances Tse (McMaster University) provided guidance for balancing thrombotic risk with upper GI bleeding risk in patients on anti-platelet agents, focussing on a few frequently asked questions. Should anti-platelet therapy be withheld and, if so, when should it be restarted? When used for secondary prevention, acetylsalicylic acid (ASA) should be restarted within 7 days of an upper GI bleed. For primary prevention, the risk of bleeding likely outweighs the risk of a cardiovascular event; therefore ASA should probably be withheld. How can anti-platelet therapy be managed (to reduce the risk of upper GI bleeding)? The COGENT trial, although stopped early for financial reasons, showed that a proton pump inhibitor with dual anti-platelet therapy decreased the risk of upper GI bleeding, with no significant increase in cardiovascular events. Should anticoagulation be reversed (partially, completely)? Should we wait for coagulopathy to be reversed before we do endoscopy? Based on limited data, the international guidelines recommend that coagulopathy be corrected; however, endoscopy should not be delayed in patients receiving an anticoagulant. Should anticoagulation be restarted and, if so, when? The benefits of resuming warfarin following an upper GI bleed outweigh the risks; however, the optimal timeframe to restart is not clear. Warfarin should likely be restarted within 7 days, but this decision should be based on clinical judgment. New oral anticoagulants (NOACs) have several benefits over warfarin (half-life, onset, fewer drug-drug interactions) and may be considered as an alternative. At present, they lack an antidote and the optimal time to restart NOACs is also unclear. Variceal bleeding an update Dr. Samir Grover (University of Toronto) presented data showing that patients treated to a restrictive transfusion threshold (70 g/l, targeting a hemoglobin of 70-90 g/l) had better survival than patients treated to a liberal transfusion threshold (90 g/l, targeting 90-110 g/l). The 2007 American Association for the Study of Liver Diseases guidelines recommend a threshold of 80 g/l. While a transjugular intrahepatic portosystemic shunt (TIPS) is indicated for secondary prophylaxis, and as rescue therapy, it is also being studied for earlier use (within 72 hours of admission in patients at high risk for alternative treatment failure after initial medical and endoscopic therapy). A randomized, controlled trial showed the early TIPS group experienced significantly greater control of bleeding. Early TIPS should only be performed: in centres with significant experience, in the absence of good rescue measures, in patients without contraindications, and when hepatic and portal vein anatomy is identified. Two methods of rescue therapies for variceal bleeding were presented: hemostatic powder and self-expandable metallic stents. Both are currently supported by limited evidence, but are being evaluated. Small Bowel Bleeding While guidelines for small bowel bleeding exist, management varies widely. Repeat endoscopy rarely identifies lesions, while repeat gastroscopy often identifies missed lesions and is not invasive. Dr. Dana Moffat (University of Manitoba) recommended push enteroscopy as the first test in most scenarios, although this method achieves an incomplete evaluation of the small bowels. Other imaging modalities include: small-bowel follow-through, CT enterography, CT angiography, nuclear medicine scanning, angiography, balloon-assisted enteroscopy and video capsule endoscopy (VCE). Video capsule endoscopy is able to evaluate the entire small bowel and has a high sensitivity for finding the source of the lesion. However, nothing can be done to treat the lesion using VCE and it is less precise in terms of lesion location. If possible, VCE should be done early. Repeat capsules are an option after an incomplete evaluation, ongoing bleeding or for follow-up. After a negative capsule (i.e. no lesion identified) re-bleeding rates are very low. A negative capsule is a predictor of no significant lesions and action may not be required. Capsules can miss dysplasia in the small bowel that isn t actively bleeding. In high-risk patients a second imaging modality should be used. Lower GI Bleeding Colonoscopy is the best test for the majority of patients who present with lower GI bleeding. It has an excellent diagnostic yield and good safety. The radiographic modalities rely on active bleeding at the time of the exam and are only appropriate in patients with significant bleeding. Dr. Lisa Strate (University of Washington) provided an algorithm for assessing patients based on risk level (see Figure 4). Figure 4. Imaging in lower gastrointestinal bleeding Low risk Colonoscopy urgent High risk Exclude upper GI Stable Unstable Angiography CT angiography Tagged scan Data has shown that urgent colonoscopy (within 12-24 hours) improved outcomes and diagnostic yield in severe diverticular bleeding. The best results were achieved with an aggressive preparation, but only in patients who could tolerate it. Unprepared colonoscopy has achieved good results in a small study and endoscopic clipping also seems to be effective in diverticular bleeding. Factors which have been consistently associated with poor outcome in lower gastrointestinal bleeding include: markers of hemodynamic instability, evidence of ongoing bleeding and comorbid illness. These patients should be triaged for urgent interventions.
IBD: Ulcerative Colitis Session co-chaired by Dr. John Marshall (McMaster University) and Dr. Brian Bressler (University of British Columbia). Biologics New and Old: Selecting Therapy in 2014 The majority of patients with UC are not in remission after 6 months of tumour necrosis factor (TNF) antagonist therapy. Dr. Brian G. Feagan (Western University) reviewed biologic options that may meet the needs of these patients. There are two new, fully human, subcutaneous TNF antagonists for the treatment of UC. Significantly more patients with UC were in remission with golimumab vs. placebo (PURSUIT) or adalimumab vs. placebo (ULTRA-1 and -2), which was maintained for ~1 year. Among the TNF antagonists, subcutaneous agents have the benefit of selfadministration, while intravenous agents (i.e. infliximab) have better adherence. α 4 β 1 and α 4 β 7 integrins mediate leukocyte adhesion and trafficking through vascular cell adhesion molecule 1 (VCAM-1), fibronectin and mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) (see Figure 5). Natalizumab, an α 4 -integrin antagonist, looked promising but was associated with progressive multifocal leukoencephalopathy (PML), a serious central nervous system infection. Although patients at risk of PML can now be identified through JCV serology, this observation slowed clinical development. In contrast, vedolizumab, an α 4 β 7 antagonist, shows gut specificity; thus no risk of PML. In a phase III study, significantly more patients on vedolizumab vs. placebo achieved remission, regardless of prior TNF antagonist exposure. Other anti-adhesion molecules are also in development. Figure 5. Adhesion receptors α 4 β 1 weak binding VCAM-1 Adapted from: Springer TA. Cell. 1994;76:301-14. α 4 β 7 MAdCAM-1 For in-hospital patients, infliximab will remain the gold standard. For ambulatory patients, biologic options will include infliximab, adalimumab, golimumab and vedolizumab. The choice between subcutaneous and intravenous TNF antagonist is left to physician discretion. Vedolizumab may be safer than TNF antagonists, but 5-10 years of cumulative data will be required before clear recommendations can be established. Dysplasia Surveillance: Do we need it? Current guidelines for IBD, recommending colonoscopy with random biopsies to detect dysplasia, are outdated. Dr. David T. Rubin (University of Chicago) noted that random biopsies are of limited value and most dysplasia is visible in white light. When detected, raised dysplasia can be resected without requiring a colectomy (see Figure 6). Figure 6. Approach to visible dysplasia in IBD High Colectomy Endoscopic appearance? Flat Grade? Yes Low Multi-focal? Colectomy vs. aggressive followup Polyp Complete endoscopic resection Colonoscopy 6 months Adapted from: Rubin et al. Clin Gastroenterol Hepatol. 2006;4:1309-13. The field is also moving towards more descriptive terms for dysplasia, such as polypoid, non-polypoid, flat and invisible; these terms should be discussed with pathologists. Data shows that the risk of colorectal cancer in IBD patients may not be as high as originally believed. This may be due to improved surveillance and prevention strategies. Dr. Rubin provided his approach to chromoendoscopy, which he uses in high-risk patients (primary sclerosing cholangitis or previously confirmed dysplasia) or for lesions that require clarification. Dysplasia surveillance is needed, but patients should be stratified based on risk to determine the frequency and method of surveillance. There will be an international consensus meeting on colorectal neoplasia in IBD in March 2014 to provide new recommendations. New Targets in UC Therapy Clinical trials in UC are moving toward more stringent outcome measures; however, in a recent European survey, a minority of respondents were using endoscopic or biomarker treatment targets. Dr. Mark S. Silverberg (University of Toronto) presented data showing that a surprising number of patients with inactive UC (according to clinical remission criteria) had poor quality of life due to ongoing symptoms. Such symptoms can lead to disease extension, exacerbations, dysplasia/neoplasia and dysmotility. Multiple studies have shown a poor correlation between endoscopic disease activity and symptoms. Serum and fecal biomarkers are a means for monitoring mucosal healing, and, in conjunction with endoscopic parameters, should be used to devise patient management strategies. Currently, there are no commercially-available tests for genetic/genomic markers of mucosal healing. When monitoring C-reactive protein levels, the overall trend is more important than the absolute value. C-reactive protein is more useful in Crohn s disease than UC. Fecal markers are new in Canada and can be used to predict disease relapse, but currently they are not covered in most provinces. Dr. Silverberg suggested treating to mucosal healing in patients with high-risk features (prior hospitalization, recent steroid use, poor response to steroids, persistent elevation in markers, extensive/extending UC) and to clinical remission in low-risk patients. No IBD: Ulcerative Colitis 6
Canadian Association for the Study of the Liver CDDW DIGEST CASL ACEF Association Canadienne pour l étude du foie CDDW Gold Sponsors: Produced and Published by: www.meducom.ca Copyright 2014 The information contained in this report is intended to reflect content from selected sessions at the 2014 Canadian Digestive Diseases Week and the Annual CASL Winter Meeting held in Toronto, Ontario, February 8-11, 2014. Any therapeutics mentioned in this report should be used in accordance with federally approved prescribing information. Please consult respective product monographs for complete dosage and official product information. No claims or endorsements are made for any products, indications or dosages not approved in country of usage or presently under investigation. No endorsement is made or implied by coverage of such unapproved use. Information provided herein is not intended to serve as the sole basis for individual care. No responsibility is taken for errors or omissions in this publication. No part of this report, either in whole or in part, may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, recording or otherwise, without the written permission of the Canadian Association of Gastroenterology and the Canadian Association for the Study of the Liver.